Lisa Osborne
Relevant Thesis-Based Degree Programs
Affiliations to Research Centres, Institutes & Clusters
Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
The combination of diverse metabolism, large microbial community, and vast surface area make the intestines a complex immunological challenge. Mucosal immune responses must target infections while limiting disruptions to intestinal function or off-target reactions in the antigen-rich environment. Regulation of this balance, which is shaped locally by tissue-specific cues, and distally in secondary lymphoid organs, is not fully understood. Exploring these concepts promises insights into vaccine development and treatment of inflammatory digestive diseases. Intestinal epithelial cells (IECs) not only maintain a barrier between the external environment and host tissues, they are also active participants in local immune homeostasis. Based on prior observations that IEC-intrinsic canonical and non-canonical NF-κB activation via the kinases IKKβ and IKKα shape the inflammatory tone of immune responses to helminth and bacterial infections, I hypothesized that IEC-intrinsic NF-κB signalling may be a conserved mediator of inflammation elicited by enteric infections. However, in the context of acute or persistent intestinal murine norovirus (MNV strain CW3 or CR6) infection, there was no detectable effect on viral loads or antiviral CD8⁺ effector T cells in the absence of either IKKα or IKKβ in IECs. To assess how antiviral CD8⁺ T cell distribution along the length of the gastrointestinal (GI) tract is regulated, I used tissue microscopy and flow cytometry following infection with MNV CW3 and CR6. I found that the initial intestinal site of infection dictates which node of the mesenteric lymph node (MLN) complex hosts the earliest CD8⁺ T cell responses. However, later stages of T cell expansion and localization within the GI tract are driven by virus-specific behavior. My results suggest that in the absence of systemic infection, antiviral effector cells primed in the spleen are not equipped for intestinal access. Understanding how intestinal access is granted will be valuable in designing oral vaccines while methods of enforcing intestinal immune seclusion may provide a means of preventing or limiting flareups in people with inflammatory digestive diseases. This work outlines avenues of inquiry using MNV strains in a comparative model to contrast CD8⁺ T cell responses and delineate cues which influence the distribution and scale of immune responses.
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Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Bacteriophages (phages) are viruses that infect bacteria with species- and strain-level specificity and are the most abundant biological entities across all known ecosystems. Within bacterial communities, such as those found in the gut microbiota, phages are implicated in regulating microbiota population dynamics and driving bacterial evolution. The specificity of phage-bacterial interactions has generated renewed interest in phage research as a potential alternative strategy to counter the increasing threat of antimicrobial resistant bacteria. While there has been some success in using phage therapy to combat bacterial septic infections, we still do not have the foundational understanding of phage-bacteria-host dynamics within our gut ecosystems that is needed for their safe development.Recent studies demonstrating that phages adhere to intestinal mucus through specific capsid proteins (Hoc) have suggested that phages may protect the underlying epithelium from bacterial invasion, providing a host-extrinsic mechanism to maintain intestinal homeostasis. Here, I build upon these findings to investigate the kinetics between Escherichia bacteriophage T4 (containing a Hoc domain) and its target bacterium, Escherichia coli, within the intestinal tract of a gnotobiotic mouse model. I determined that T4 phage and E. coli can stably coexist within the murine gastrointestinal tract in the absence of other microbes, despite continual phage predation. However, I was unable to conclude that T4 phage retention within the murine gut requires Hoc protein-mediated mucus adhesion. Further, my data suggest that gut-colonising T4 phage elicit a type 1 immune response in the gut-draining lymph nodes, without causing inflammatory disease. Together, these results suggest that T4 phage is well tolerated in the gastrointestinal tract of gnotobiotic mice by the bacterial and metazoan hosts and may contribute to immune system priming.
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Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) that causes demyelination of neurons, neurodegeneration and progressive disability. The exact cause of Multiple Sclerosis remains unknown however, susceptibility to MS is influenced by genetics and environmental factors, such as diet. As zero-fiber diets have been associated with exacerbated disease in inflammatory disease models, we investigated dietary fiber’s impact on the murine model of MS, experimental autoimmune encephalomyelitis (EAE). We demonstrated that standard fiber diets (5%) do not offer protection against EAE when compared to zero-fiber diets, whereas a diet high in the soluble fiber, guar gum (30%), inhibited disease progression and prevented lymphocytic CNS infiltration. Other soluble fibers: pectin, resistant starch and inulin did not offer the same protection – providing evidence that the types of dietary fiber have differential effects on the immune system and neuroinflammation.
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Mammalian evolution has occurred while hosting mutualistic, commensal, and pathogenic micro- and macro-organisms for millennia. The virome can provide beneficial immune-stimulating signals or it can provide detrimental immune-stimulating signals that impact host health. Mechanisms that are important for relaying signals from the virome to the immune system are not well understood. Here I investigate the importance of a signalling molecule, Signal Transducer and Activator of Transcription-1 (STAT1), in controlling the immune response to an asymptomatic and persistent virus infection by murine Norovirus strain CR6 (CR6). By evaluating clinical parameters and virus-specific adaptive immune responses I was able to better understand how the host can coordinate appropriate immune responses to persistent enteric virus infections. Moreover, I confirmed that host-virome signals could limit CR6 burdens and systemic dissemination in immunosufficient mice. I conclude with a new perspective of how CR6 persists asymptomatically; by therapeutically limiting CR6 replication, I uncovered that unlike other persistent virus infections CR6 persistence may not be due to the apparent weak immune responses against it. Importantly, CR6 persistence requires STAT1 signalling, because deficient signalling leads to uncontrolled virus replication and ultimately host mortality, which limits virus transmission potential
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